PROPOSAL (Adapted from the applicant's abstract): The long-term goal of the candidate is to pursue a career in academic medicine in the field of endocrinology and metabolism with a specific research goal of becoming an independent researcher in the area of fuel metabolism and obesity. The candidate's immediate goals are to develop the strong foundation and skills necessary for the transition to an independent research career. The Mentored Patient-Oriented Research Career Development Award will help to enable the candidate to reach these short-term goals by completing the proposed studies and following the specific career development plan outlined. In addition, the institution and mentors provide an outstanding and supportive environment. The goal of the proposed research project is to gain a better understanding of the effects of short-term overfeeding on nutrient metabolism. Obesity is a serious and growing public health problem in the U.S. The pathophysiological processes that underlie this increasing prevalence of obesity have not been clearly defined but likely involve faulty interactions between environmental factors, which favor positive energy balance, with biological weight regulatory systems in genetically "at risk" individuals. Individuals who are genetically predisposed to leanness in the current environment may be able to sense and respond to excess energy intake more rapidly and accurately than those predisposed to obesity. It is hypothesized that lean individuals develop transient insulin resistance in response to overfeeding and may preferentially deliver dietary fat to oxidatively active tissues, leading to increased fat oxidation. This may also be associated with an increased sense of satiety in these individuals as well. The end result is that these mechanisms will protect lean individuals from excessive weight gain. To test these ideas, studies of lean and reduced-obese subjects, following a three-day period of overfeeding 50% above basal caloric requirements, are proposed. Specifically, studies on the insulin sensitivity of lipolysis, glucose disposal, and glucose production using insulin clamp and tracer techniques, as well as tracer meal studies examining the metabolic fate of labeled glucose and fatty acids, are proposed. These studies will include indirect calorimetry, tracer oxidation, limb balance, and tissue sampling to give a comprehensive view of meal associated nutrient metabolism. Complementary studies on the effects of overfeeding on satiety and palatability are also proposed. These studies will provide insight into the biology that predisposes to weight gain and regain and will lay the groundwork for future studies of the abnormalities in nutrient metabolism that exist in obese and preobese individuals.